Diabetic macular edema (DME) is an accumulation of fluid in the macula of patients with diabetic retinopathy (DR), which can occur at any stage of the disease. DR is one of the most common microvascular complications of diabetes. Vision-threatening DR (i.e. DME and proliferative diabetic retinopathy (PDR) is the leading cause of visual disability and blindness among working-aged adults around the world. Globally, the overall prevalence of DR is estimated at 34.6% of the people with diabetes, while the overall prevalence of DME is estimated at approximately 20% of the people with DR (Yau et al., 2012). The prevalence of DME is expected to rise further due to the increasing prevalence of diabetes, ageing of the population and increased life expectancy of people with diabetes: the number of adults with diabetes worldwide was estimated at 425 million in 2017 and is expected to increase to 629 million by 2045.
Although the exact mechanisms by which diabetes causes retinopathy remains unclear, several studies have shown the elevation of reactive oxygen species, advanced glycation end products and circulating and vitreous cytokines and chemokines in relation to the disease. Inflammation in the retina is a major early pathological hallmark of DR. Inflammatory and vasodilator factors can modify endothelial function, leading to blood-retinal barrier breakdown, which results in accumulation of plasma proteins and lipids into the macula. When the thickening involves the fovea or threatens to involve the fovea, the patient becomes symptomatic with metamorphopsia and vision loss.
The interaction between the vitreous and the retina has been found to be involved in the development of macular edema. In particular, when the vitreous and the macular area of the retina are tightly conjugated, macular edema can be greatly promoted. Among patients with DR, DME was present only in 20% of patients with posterior vitreous detachment (PVD) as compared to in 55% of patients without PVD, suggesting a strong protective effect of PVD. The proposed mechanism for potential benefit of PVD is the relief of vitreomacular traction, however, both transvitreal oxygenation and improved growth factor diffusion (away from the pre-macular hyaloid) have also been suggested to potentially have beneficial effects.
Good control of blood glucose, blood pressure and blood lipids is essential and can delay the onset of DR and slow its progression. Treatment occurs in some cases by focal/grid laser photocoagulation using small, light-intensity laser burns (50-100 μm) to micro-aneurisms or diffuse areas of thickening. However, this treatment could result in complications such as loss of central vision, central scotomas and decreased color vision. More recently, subthreshold micropulse laser has been developed as a treatment that theoretically avoids damaging the inner neurosensory retina, thereby reducing potential complications.
Several pharmacologic agents are now available for the treatment of DME, including anti-vascular endothelial growth factor (VEGF) agents and corticosteroids. VEGF is a potent vasopermeability factor contributing to the macular thickening and visual impairment associated with DME. Anti-VEGF compounds decrease angiogenesis and vascular permeability, causing regression of neovascularization and reduction of edema. Several clinical studies have shown that anti-VEGF treatment is more effective than focal/grid laser treatment at decreasing central subfield thickness (CST) and improving vision in DME patients. Adverse events (AEs) related to anti-VEGF treatment are rare and mostly related to the need for repeated intravitreal (IVT) injections over a prolonged period of time.
Inflammation plays an important role in the pathogenesis of DME. Cytokines and chemokines released by leukocytes in the blood significantly increase vascular permeability leading to more fluid build-up under the retina. Corticosteroid therapies can inhibit inflammatory mediators. Several clinical studies have shown that corticosteroids are effective in decreasing CST and improving vision in DME. While the treatment burden of corticosteroid implants is much lower than that of anti-VEGF agents, intraocular corticosteroids are associated with increased risks of cataract development and elevation of intraocular pressure. Overall, the use of IVT corticosteroids in patients with DME is therefore reserved as a second-line therapy in those who respond poorly to IVT anti-VEGF therapy and is contraindicated in patients with underlying glaucoma.
Of the possible treatments of DME mentioned above, the anti-VEGF agents are currently the first-line gold standard treatment for DME. Most studies to date however report that a substantial proportion of DME patients, up to 40%, have persistent edema and loss of visual acuity despite anti-VEGF treatment. These findings suggest that other pathways, independent of VEGF, contribute to the development of DME, and there is thus an important clinical need for additional effective treatments for DME.
Integrins constitute a family of transmembrane cell surface receptors that can mediate cell-cell and cell-extracellular matrix interactions. Integrins are involved in various biological processes including cell differentiation, adhesion, shape, migration, motility, invasion, proliferation, and survival. Because of their role in these biological processes, integrins have also been associated with various pathological conditions, such as cancer and ophthalmic disorders. In the eye, integrins have been shown to play an important role in neovascularization, vascular permeability and vitreoretinal adhesion.
Integrins are obligate heterodimeric receptors consisting of a non-covalently bound α and β subunit. Different combinations of the 18 α and the 8 β known subunits constitute the family of 24 heterodimeric integrin members recognized thus far. The integrin family of receptors can be broadly classified into 4 different categories depending on their ligand recognition pattern: 1) the tripeptide L-arginine-glycine-aspartic acid (RGD) binding, 2) collagen binding, 3) laminin binding and 4) leukocyte binding types of integrins.
Interaction of integrins with the extracellular matrix can lead to neovascularization of the retinal surface, which can eventually extend towards the vitreous region. Immunohistological staining on human retinal tissues derived from PDR patients has shown that actively proliferating vascular endothelial cells express the integrins αvβ3 and αvβ5, which are not highly expressed in quiescent endothelial cells (Friedlander et al., 1996; Ning et al., 2008). In addition, αvβ3 and αIIbβ3 have been shown to be expressed in fibrovascular epiretinal membranes from patients with active PDR in the fibrotic stage (Ning et al., 2008; Abu El-Asrar, Missotten and Geboes, 2010), whereas α5β1 has been shown to be overexpressed in a laser-induced mouse model of CNV (Umeda et al., 2006). In line with this, several non-clinical studies have demonstrated that inhibition of integrins attenuates leukostasis and retinal vascular permeability (Santulli et al., 2008; Iliaki et al., 2009; Rao et al., 2010). Antagonism of αvβ3 and αvβ5 prevented retinal neovascularization but did not harm pre-existing blood vessels (Friedlander et al., 1996; Hammes et al., 1996; Lahdenranta et al., 2007; Santulli et al., 2008), whereas inhibition of α5β1 inhibited endothelial cell proliferation and produced regression of choroidal neovascular membranes in different animal models (Ramakrishnan et al., 2006; Umeda et al., 2006).
The RGD motif is very commonly found in many components of the extracellular matrix, including vitronectin, fibronectin and fibrinogen. Integrins are therefore heavily linked to extracellular matrix proteins, thereby mediating cell-extracellular matrix adhesion, for instance in the vitreoretinal interface. Analogues of the RGD motif are known to compete for the RGD motif of extracellular matrix proteins to disrupt integrin-extracellular matrix interactions and therefore loosen the attachments in in vitro experiments (Gehlsen et al., 1988; Pierschbacher and Ruoslahti, 1987; Zhou, Zhang and Yue, 1996). In line with this, IVT injection of soluble RGD peptides has been shown to induce PVD in rabbit eyes (Oliveira et al., 2002). Moreover, in humans, 3 IVT injections of the integrin antagonist ALG 1001 (Allegro Ophthalmics, LLC) have been shown to induce total PVD in 6 of 11 DME patients with no or partial PVD at baseline in an initial proof-of-concept study (Kuppermann, 2013; Boyer et al., 2014).
These observations underpin the preference for using a pan-integrin antagonist that targets the different types of integrins that underlie different aspects of the disease to be treated, most notably αvβ3, αvβ5 and α5β1. The complexity is that such pan-integrin antagonists will often also antagonize other RGD-binding integrins, which may cause side effects. Most notable is the platelet integrin, αIIbβ3, whose antagonism may interfere with platelet activation and aggregation.
Patent application publications WO2011/119282 A1, WO2011/094285 A1, US2006/0052398 A1 and US2008/058348 A1 disclose compounds as potential integrin antagonists or as potential vitronectin receptor antagonists. The compounds disclosed in these patent applications can be summarized as generally corresponding to Formula A

wherein, generally G1 represents a substituted pyridine or tetrahydro naphtyridine, R1 and R2 are hydrogen, methyl or ethyl, and R3 is a hydrophobic tail group. In particular, in the exemplified compounds with confirmed activity, R3 comprises an alkyl, cycloalkyl or (hetero)aromatic end group.
There is a need for novel integrin antagonists, in particular integrin antagonists that act simultaneously on the different types of integrins that are involved in disease pathways, such as αvβ3, αvβ5 and α5β1, but which have a reduced risk of interfering with platelet aggregation through their effect on αIIbβ3.